The invention relates to new therapeutic compounds, in particular to antithrombotic agents, a process for their preparation, pharmaceutical compositions containing the compounds as active ingredients, as well as the use of said compounds for the manufacture of medicaments.
In therapy, a multiplicity of active compounds is used for the treatment and prophylaxis of all sorts of diseases. Drugs differ widely in their pharmacodynamic effects and clinical application, in penetrance, absorption and usual route of administration, in distribution among the body tissues and in disposition and mode of action.
Apart from the type of patient and the type of disease to be treated or to be prevented, the physicochemical properties of therapeutically active compounds determine to a great extent the preferred route of their admistration. In the development of drugs, the oral applicability thereof is usually an important selection criterium. For the majority of patients this is obviously the most convenient route for access of the drug to the systemic circulation. In order for a drugxe2x80x94administered via oral routexe2x80x94to act, it must first be absorbed before it is transported to the appropriate tissue or organ, where it may penetrate to the responding subcellular structure and may subsequently be metabolized, or where it may be bound, stored, or whatever is necessary to elicit a response or to alter ongoing processes. However, not always compounds which have been found to possess an advantageous therapeutic activity are also sufficiently absorbed in the gastrointestinal tract to display effective oral bioavailability.
Thus, one of the pivotal issues in drug design is to develop compounds which both show activity and good absorptive properties. An important area in which is actively sought for oral biavailability is the area of antithrombotic agents.
The present invention relates to antithrombotic compounds comprising the group Q, Q having the formula 
wherein the substructure 
is a structure selected from 
wherein X is O or S;
Xxe2x80x2 being independently CH or N;
and m is 0, 1, 2 or 3;
wherein the group Q is bound through an oxygen atom or an optionally substituted nitrogen or carbon atom,
or a pharmaceutically acceptable salt thereof or a prodrug thereof
The compounds of the invention are active antithrombotic agents having an improved pharmacological profile, in particular with regard to properties like their absorptive properties and their toxicity.
The term xe2x80x9cantithrombotic compoundxe2x80x9d means any compound having antithrombotic activity. Examples of such compounds are inhibitors of serine proteases that play a role in the blood coagulation cascade or GpIIb/IIIa antagonists.
The group Q is bound to the molecule through an oxygen atom or an optionally substituted nitrogen or carbon atom. xe2x80x9cOptionally substitutedxe2x80x9d in this respect means any suitable substituent, such as, but not limited to, oxo, alkyl, alkenyl, alkoxy, aryl, halogen and the like,
The term xe2x80x9cprodrugxe2x80x9d means a compound of the invention in which (an) amino group(s) is (are) protected, e.g. by (a) hydroxy or (1-6C)alkoxycarbonyl group(s), or a compound whereinxe2x80x94if presentxe2x80x94(a) carboxylate group(s) is (are) esterified.
The present invention relates to the surprising finding that the presence of the group Q in antithrombotic compounds gives rise to favourable properties of the compounds. Especially when Q is used to replace a basic moiety in compounds of which is known that they require such a moiety for their activity, an improvement of the pharmacological properties is realized, and in particular when that basic moiety is a (hetero)arylguanidino or (hetero)arylamidino moiety. In particular an improvement of the absorptive properties of those compounds is observed. Also a reduction of the toxicity of compounds of this invention is observed.
Preferably the group Q has the formula 
m being as previously defined.
An established in vitro model for the determination of the absorptive properties of drugs is the Caco-2 model (Artursson, P., S.T.P. Pharma Sciences 3(1), 5-10, 1993; Walter, E et al. Pharmaceutical Research, 3, 360-365, 1995). In this in vitro model the transepithelial transport properties of a compound are determined in monolayers of a human intestinal cell-line (Caco-2) in terms of a permeability coefficient (apparent permeability). This model is useful for the prediction of in vivo absorption of compounds in the gastrointestinal tract. Preferably the antithrombotic compounds of the invention have a Caco-2 permeability of 8 nm/s or higher.
As noted above, amongst the compounds of the present invention are inhibitors of serine proteases of the blood coagulation cascade, and in particular inhibitors of thrombin and/or factor Xa. Preferred compounds inhibit thrombin more effectively than other serine proteases. More preferred compounds are thrombin inhibitors having, in addition, an IC50 value of less than 1 xcexcM. The compounds are useful for treating and preventing thrombin-mediated and thrombin-associated diseases. This includes a number of thrombotic and prothrombotic states in which the coagulation cascade is activated which include, but are not limited to, deep vein thrombosis, pulmonary embolism, thrombophlebitis, arterial occlusion from thrombosis or embolism, arterial reocclusion during or after angioplasty or thrombolysis, restenosis following arterial injury or invasive cardiological procedures, postoperative venous thrombosis or embolism, acute or chronic atherosclerosis, stroke, myocardial infarction, cancer and metastasis, and neurodegenerative diseases. Compounds of the invention may also be used as in vitro anticoagulants or as anticoagulants in extracorporeal blood circuits, such as those necessary in dialysis and surgery.
Serine proteases are enzymes which play an important role in the blood coagulation cascade. Apart from thrombin and factor Xa, other examples of this group of proteases comprise the factors VIIa, IXa, XIa, XIIa, and protein C.
Thrombin is the final serine protease enzyme in the coagulation cascade. The prime function of a thrombin is the cleavage of fibrinogen to generate fibrin monomers, which are cross-linked to form an insoluble gel. In addition, thrombin regulates its own production by activation of factors V and VIII earlier in the cascade. It also has important actions at cellular level, where it acts on specific receptors to cause platelet aggregation, endothelial cell activation and fibroblast proliferation. Thus thrombin has a central regulatory role in homeostasis and thrombus formation. Since inhibitors of thrombin may have a wide range of therapeutical applications, extensive research is done in this area.
In the development of synthetic inhibitors of serine proteases, and more specifically of thrombin, the benzamidine moiety is one of the key structures. It mimics the protonated side-chain of the basic amino acids Arg and Lys of its natural substrates. Compounds with this moiety have been studied extensively and repeatedly. A very potent representative of this type of thrombin inhibitors is the amino acid derivative Nxcex1-(2-naphthylsulfonyl)-glycyl-4-amidinophenylalanin-piperidide (NAPAP) (Stxc3xcrzebecher, J. et al., Thromb. Res. 29, 635-642, 1983). However, the pharmacological profile of NAPAP is unattractive for therapeutical applications: the compound shows toxic effects after intravenous administration and, in addition, poor oral bioavailability after oral administration. Up until now, the NAPAP-like benzamidine derivatives which have been investigated for use as thrombin inhibitors show these unfavourable pharmacological and pharmacokinetic properties. It was assumed that these properties are due to the strong basicity of the amidino functionality of these compounds (Kaiser, et al., Pharmazie 42, 119-121, 1987; Stxc3xcrzebecher, J. et al., Biol. Chem. Hoppe-Seyler, 373, 491-496, 1992). Several studies have been performed on variations of this basic structure (see for example Stxc3xcrzebecher, J. et al., Pharmazie 43, 782-783, 1988; Stxc3xcrzebecher, J. et al. (1993), DIC-Pathogenesis, Diagnosis and Therapy of Disseminated Intravascular Fibrin Formation [G. Mxc3xcller-Berghaus et al., eds.] pp. 183-190, Amsterdam, London, New York, Tokyo: Exerpta Medica). However, modifications of the benzamidine moiety decreasing its basicity always resulted in a drastic loss of anti-thrombin activity (Stxc3xcrzebecher, J. et al., J. Enzyme Inhibition 9, 87-99, 1995).
Oral bioavailability is a property of thrombin inhibitors which is urgently searched for. Potent intravenous thrombin inhibitors are clinically effective in acute care settings requiring the treatment of thrombin-related diseases However, particularly the prevention of thrombin-related diseases such as myocardial infarct, thrombosis and stroke require long-term therapy, preferably by orally dosing an anticoagulant. Consequently, the search for active, orally bioavailable thrombin inhibitors continues unabated. Oral bioavailability is at least in part related to the ability of compounds to be absorbed in the gastrointestinal tract. The low oral bioavailability of NAPAP and its analogues may therefore be related to their deficient absorptive properties in the intestines.
The present invention provides a solution to the deficient pharmacological properties of the NAPAP-like compounds, in particular with respect to the toxicity and the deficient absorptive properties.
Preferred serine protease inhibitors of the invention have the formula (I), comprising the group Q; compounds of this type show improved transepithelial transport properties (increased apparent permeability) in comparison with prior art compounds:
R1xe2x80x94Yxe2x80x94[NR2xe2x80x94Axe2x80x94C(O)]nxe2x80x94NR3xe2x80x94CHR4xe2x80x94C(O)xe2x80x94R5xe2x80x83xe2x80x83(I)
wherein R1 is (1-8C)alkyl, (6-14C)aryl-(1-8C)alkenyl, (6-14C)aryl-(1-8C)alkanoyl, (6-14C)aryl, (7-15C)aralkyl, bisaryl, heteroaryl, heteroaralkyl(1-8C)alkyl, heterocycloalkyl, cycloalkyl or cycloalkyl substituted alkyl; R2 is H or (1-8C)alkyl; R3 is Q when R4 is H, or R3 is H or (1-8C)alkyl when R4 is Q; Q is as previously defined; R5 is OH or OR6, R6 being (1-8C)alkyl (3-12C)cycloalkyl or (7-15C)aralkyl, or R5 is NR7R8, wherein R7 and R8 are the same or different being H, (1-8C)alkyl, (3-12C)cycloalkyl, (6-14C)aryl, (7-15C)aralkyl, optionally subtituted with (1-8C)alkoxy, C(O)OH or C(O)OR6, or R7 and R8 together with the nitrogen atom to which they are bonded are a nonaromatic (4-8)membered ring optionally containing another heteroatom, which ring may be condensed with another optionally aromatic ring and may be subtituted with OH, an oxo group, (1-8C)alkyl, optionally substituted with one or more halogens or hydroxy groups, (2-8C)alkenyl, (1-8C)alkylidene, (2-8C)alkynyl, (1-8C)alkoxy, (1-8C)acyl, (6-14C)aryl, C(O)OH, C(O)OR6, C(O)NR9R10, wherein R9 and R10 are the same or different being H or (1-8C)alkyl, or SO2R11 and R11 is (1-8C)alkyl optionally substituted by one or more fluorine atoms; Y is SO2 or C(O); A is CHR12, R12 being H, phenyl, benzyl, (1-8C)alkyl, optionally substituted with OH or COR13 wherein R13 is OH, (1-8C)alkoxy, morpholino, morpholino(1-8C)alkoxy, NH2, NHR14 or NR14R15, R14 and R15 being independently (1-8C)alkyl optionally substituted with C(O)OR2 or R14 and R15 are a nonaromatic (4-8)membered ring together with the nitrogen atom to which they are bonded, or R12 together with R3 is xe2x80x94(CH2)sxe2x80x94 when R4 is Q, s being 2, 3 or 4, or A is NR2;
and n is 0 or 1, or a pharmaceutically acceptable salt thereof.
Related thrombin inhibitors are disclosed in WO 92/16549 and WO 92/08709, wherein respectively para- and meta-substituted phenylalanine derivatives are described having an amidino, guanidino, oxamidino, aminomethyl or amino substituent. However, compounds with the amidino substituent show unfavourable pharmacological properties, whereas the other structures, with a modified amidino moiety, display a loss of activity (vide sipra). Other modifications are described in EP 555824 where compounds are disclosed having a benzimidazolyl group, which compounds do not contain a primary amino functionality.
Thrombin inhibitors having a benzamidine moiety have also been modified in other parts of the molecule, however, without improvement of the unfavourable pharmacological properties caused by the amidino substituent. Examples hereof are disclosed in EP 508220, wherein the compounds contain an azaglycyl group instead of the glycyl group of NAPAP; in DE 4115468, wherein that glycyl group is replaced e.g. by an aspartyl group; in WO 94/18185, wherein no glycyl group is present in the compounds and the piperidine group which is present in NAPAP is replaced by a piperazide group; in WO 95/13274, wherein the compounds also do not have a glycyl group and modifications are madexe2x80x94in comparison with NAPAPxe2x80x94in the arylsulfonyl part and the piperidine part of the molecule, and in EP 236163, wherein Nxcex1-alkyl substituted amidinophenylalanin derivatives are described. Furthermore, Stxc3xcrzebecher, J. et al. (Thrombosis Research 54, 245-252, 1989) suggest that the alkylene linkage connecting the benzamidine moiety to the rest of the molecule may have a length of 1-3 methylene groups.
Therefore, there is a still need for serine protease inhibitors, especially thrombin inhibitors, with more favourable pharmacological properties, such as the inhibitors of the present invention which potentially have good oral bioavailability
Preferred compounds of formula (I) are compounds wherein R1 is phenyl, naphthyl, (iso)quinolinyl, tetrahydro(iso)quinolinyl, 3,4-dihydro-1H-isoquinolinyl, 2,3,4,5-tetrahydro-1H-benzo[d]azepinyl, 2,3-dihydro-5H-benzo[f][1,4]oxazepinyl, dibenzofuranyl, chromanyl, bisaryl, each aryl being a 5- or 6-membered ring and optionally containing a O, S or N-atom, which groups R1 may optionally be substituted with one or more substituents selected from (1-8C)alkyl, (1-8C)alkoxy the alkyl group of which may be optionally substituted with an alkoxy group or an alkoxyalkyl group, phenyl-(1-8C)alkyl, tetrahydropyranyloxy, tetrahydropyranyloxy(1-8C)alkyl or NR15R16, in which R15 and R16 are independently selected from H and (1-8C)alkyl, or R1 is (1-8C)alkyl substituted with a (5-8C)cycloalkyl, (7-10C)bicycloalkyl or (10-16C)polycycloalkyl, optionally substituted with a group selected from oxo or (1-8C)alkyl; R3 is H or (1-8C)alkyl; R4 is Q; R5 is (1-8C)alkoxy, NR7R8, wherein R7 and R8 are the same or different being H, (1-8C)alkyl, (3-12C)cycloalkyl, optionally substituted with (1-8C)alkoxy or COOR6, or R5 is a group of the formula 
wherein the interrupted line represents an optional bond, B being CR17 when the optional bond is present, or B is CHR17, R17 being H, (1-8C)alkyl, optionally substituted with one or more halogens or hydroxy groups, (2-8C)alkenyl, (2-8C)alkynyl, (1-8C)acyl, or (1-8C)alkoxy, or B is O, S, or NR18, R18 being (1-8C)alkyl, (1-8C)acyl, C(O)NR9R10 or SO2-(1-8C)alkyl optionally substituted by one or more fluorine atoms.
More preferred compounds of formula (I) are compounds wherein R2 and R3 are H and Q is 
Also preferred are compounds wherein R5 is 
and B is CH2 or CH(1-8C)alkyl.
Preferred groups R1 are phenyl, naphthyl, tetrahydroisoquinolinyl, 3,4-dihydro-1H-isoquinolinyl, 2,3,4,5-tetrahydro-1H-benzo[d]azepinyl, 2,3-dihydro-5H-benzo[f][1,4]oxazepinyl, which groups R1 may optionally be substituted with one or more substituents selected from (1-8C)alkyl, (1-8C)alkoxy the alkyl group of which may be optionally substituted with an alkoxy group or an alkoxyalkyl group, phenyl-(1-8C)alkyl, tetrahydropyranyloxy, tetrahydropyranyloxy(1-8C)alkyl or NR15R16. In compounds with these preferred R1 groups, Y is preferably SO2.
When R4 is 
n preferably has the value 1. Preferably A is CH(1-8C)alkyl substituted with COR13 wherein R13 is OH, (1-8C)alkoxy, morpholino, morpholino(1-8C)alkoxy, NHR14 or NR14R15, R14 and R15 being independently (1-8C)alkyl, or A is CHR12, R12 being xe2x80x94(CH2)sxe2x80x94 together with R3 when R4 is Q, s being 2 or 3.
Other preferred compounds are compounds wherein n is 0 and R4 is 
X being as previously defined.
Most preferred are the compounds according to formula (I) wherein R1 is 
n is 1, R2 is H, A is CHCH2C(O)OH, CHCH2C(O)O(1-8C)alkyl, CHCH2C(O)morpholine, CHCH2C(O)O(1-8C)alkylene-morpholine, CHCH2C(O)NHR14 or CHCH2C(O)NR14R15, R14 and R15 being independently (1-8C)alkyl, R3 is H, R4 is 
and R5 is 
or the compounds according to formula (I) wherein R1 is selected from 
In the description of the compounds of formula (I) the following definitions are used. The term (1-8)alkyl means a branched or unbranched alkyl group having 1-8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, hexyl and octyl. The term (2-8C)alkenyl means a branched or unbranched alkenyl group having 2 to 8 carbon atoms, such as ethenyl, 2-butenyl, etc. The term (1-8C)alkylene means a branched or unbranched alkylene group having 1 to 8 carbon atoms, such as xe2x80x94(CH2)xcex1xe2x80x94 wherein xcex1 is 1 to 8, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94, etc. The term (1-8C)alkylidene means a branched or unbranched alkylidene group having 1-8 carbon atoms, such as methylene and ethylidene. The term (2-8C)alkynyl means a branched or unbranched alkynyl group having 2-8 carbon atoms, such as ethynyl and propynyl. The term (3-12C)cycloalkyl means a mono- or bicycloalkyl group having 3-12 carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl, the camphor group, etc. A preferred cycloalkyl group in the definition of R1 is the camphor group. The term (1-8C)alkoxy means an alkoxy group having 1-8 carbon atoms, the alkyl moiety having the meaning as previously defined. The term (1-8C)acyl means an acyl group having 1-8 carbon atoms, the alkyl moiety having the meaning as previously defined. Formyl and acetyl are preferred acyl groups. The term (1-8)alkanoyl means an oxo-alkyl group, the alkyl moiety having the meaning as previously defined.
The term (6-14C)aryl means an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl, which may optinally be substituted with one or more substituents such asxe2x80x94but not limited toxe2x80x94alkyl, alkoxy, the alkyl group of which may be optionally substituted with an alkoxy group or an alkoxyalkyl group (e.g the substituent groups xe2x80x94Oxe2x80x94(CH2)2xe2x80x94OCH3 or xe2x80x94Oxe2x80x94CH(CH2OCH3)2), tetrahydropyranyloxy, tetrahydropyranyloxymethyl, acyl, alkylthio, hydroxyalkyl, haloalkyl, carboxy, carboxyalkyl, carboalkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylcarbonyl, nitro, cyano, amino, dialkylamino, alkylsulfinyl and/or alkylsulfonyl (in the relevant cases alkyl is meant to be (1-8C)alkyl).
Preferred aryl groups are 
The term (7-15C)aralkyl means an aralkyl group having 7 to 15 carbon atoms, wherein the alkyl group is a (1-8C)alkyl group and the aryl group is a (6-14C)aryl as previously defined. Phenyl-(1-8C)alkyl groups are preferred aralkyl groups, such as benzyl.
The term heteroaryl means a substituted or unsubstituted aromatic group having 4 to 12 carbon atoms, at least including one heteroatom selected from N, O, and S, like imidazolyl, thienyl, benzthienyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, dibenzofuranyl, chromanyl, 
The substituents on the heteroaryl group may be selected from the group of substituents listed for the aryl group.
Heteroaralkyl groups are analogs of the (7-15C)aralkyl groups, at least including one heteroatom selected from N, O, and S
The term bisaryl in the definition of R1 means two independently chosen aryl or heteroaryl groups according to the definitions of the term aryl and heteroaryl, connected to each other by a bond or by a short bridge, having a length of one or two atoms, such as CH2, N2 or SO2, optionally substituted with a substituent as listed for the aryl group. Examples of bisaryls are biphenyl, 
The term cycloalkyl substituted alkyl in the definition of R1 means an alkyl group, preferably having 1-8 carbon atoms, carrying a mono-, bi- or polycycloalkyl group, preferably having 5-8, 7-10 and 10-16 carbon atoms, respectively, which cycloalkyl group may optionally be substituted with an oxo group and/or a substituent as listed for the aryl group.
The term heterocycloalkyl means an optionally substituted cycloalkyl group, preferably having 4 or 5 carbon atoms, further containing one heteroatom selected from O, S or N, such as tetrahydrofuran and tetrahydropyran. The substituents on the hetercycloalkyl group may be selected from the group of substituents listed for the aryl group.
The term nonaromatic (4-8)membered ring in the definition of NR7R8, where R7 and R8 together with the nitrogen atom to which they are bonded are a ring, means a ring containing the nitrogen atom and further having at most 3-7 carbon atoms, which ring may contain unsaturated bonds. Examples of such (4-8)membered rings are azetidine, pyrrolidine, piperidine, piperazine morpholine and thiomorpholine.
In the development of synthetic inhibitors of serine proteases, and more specifically of thrombin, the interest in small synthetic peptides that are recognized by proteolytic enzymes in a manner similar to that of natural substrates, has increased. As a result, new peptide-like inhibitors have been prepared, such as the transition state inhibitors of thrombin and the low molecular weight thrombin inhibitor Inogatran (Thromb. Haemostas. 1995, 73:1325 (Abs. 1633); WO 93/11152 (Example 67)), which has been disclosed to be a potent and selective thrombin inhibitor. Related compounds are described in WO 95/23609; in comparison with Inogatran and its analogs, compounds disclosed in this patent application have an aromatic group in the agmatine-like group. Although these developments already have lead to new and meaningful insights, the search for more effective and more selective, and in particular orally applicable, thrombin inhibitors still proceeds.
Thus, other preferred serine protease inhibitors of the invention are small synthetic peptides comprising the group Q, and have the formula (XX)
Jxe2x80x94Dxe2x80x94Exe2x80x94N(Rxe2x80x2)1xe2x80x94Qxe2x80x83xe2x80x83(XX)
in which formula Q is as previously defined; (Rxe2x80x2)1 is H or (1-4C)alkyl; J is H, optionally substituted D,L xcex1-hydroxyacetyl, (Rxe2x80x2)2, (Rxe2x80x2)2xe2x80x94Oxe2x80x94C(O)xe2x80x94, (Rxe2x80x2)2xe2x80x94C(O)xe2x80x94, (Rxe2x80x2)2xe2x80x94SO2xe2x80x94, (Rxe2x80x2)7OOCxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94SO2xe2x80x94, (Rxe2x80x2)7OOCxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94, (Rxe2x80x2)32NCOxe2x80x94(CH(xe2x80x2)3)pxe2x80x94, Hetxe2x80x94COxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94, or an N-protecting group, wherein (Rxe2x80x2)2 is selected from (1-12C)alkyl, (2-12C)alkenyl, (2-12C)alkynyl and (3-12C)cycloalkyl, which groups may optionally be substituted with (3-12C)cycloalkyl, (1-6C)alkoxy, oxo, OH, COOH, CF3 or halogen, and from (6-14C)aryl, (7-15C)aralkyl and (8-16)aralkenyl, the aryl groups of which may optionally be substituted with (1-6C)alkyl, (3-12C)cycloalkyl, (1-6C)alkoxy, OH, COOH, CF3 or halogen; each group (Rxe2x80x2)3 is independently H or has the same meaning as (Rxe2x80x2)2; (Rxe2x80x2)7 has the same meaning as (Rxe2x80x2)3 or is Het-(1-6C)alkyl or Het-(2-6C)alkynyl; and Het is a 4-, 5- or 6-membered heterocycle containing one or more heteroatoms selected from O, N or S; p is 1, 2 or 3; D is a bond, an amino-acid of the formula xe2x80x94NHxe2x80x94CH[(CH2)qC(O)OH]xe2x80x94C(O)xe2x80x94 or an ester derivative thereof and q being 0, 1, 2 or 3, xe2x80x94N((1-12C)alkyl)xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94N((2-12C)alkenyl)xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94N((2-12C)alkynyl)xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94N(benzyl)xe2x80x94CH2xe2x80x94COxe2x80x94, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a L- or D-amino acid having a hydrophobic, basic or neutral side chain, which amino acid may optionally be Nxe2x80x94(1-6C)alkyl substituted; or J and D together are the residue (Rxe2x80x2)4(Rxe2x80x2)5Nxe2x80x94CH(Rxe2x80x2)6xe2x80x94C(O)xe2x80x94, wherein (Rxe2x80x2)4 and (Rxe2x80x2)5 independently are (Rxe2x80x2)2, (Rxe2x80x2)2xe2x80x94Oxe2x80x94C(O)xe2x80x94, (Rxe2x80x2)2xe2x80x94C(O)xe2x80x94, (Rxe2x80x2)2xe2x80x94SO2xe2x80x94, (Rxe2x80x2)7OOCxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94SO2xe2x80x94, (Rxe2x80x2)7OOCxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94, H2NCOxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94, or an N-protecting group, or one of (Rxe2x80x2)4 and (Rxe2x80x2)5 is connected with (Rxe2x80x2)6 to form a 5- or 6-membered ring together with xe2x80x9cNxe2x80x94Cxe2x80x9d to which they are bound, which ring may be fised with an aliphatic or aromatic 6-membered ring; and (Rxe2x80x2)6 is a hydrophobic, basic or neutral side chain; E is an L-amino acid with a hydrophobic side chain, serine, threonine, a cyclic amino acid optionally containing an additional heteroatom selected from N, O or S, and optionally substituted with (1-6C)alkyl, (1-6C)alkoxy, benzyloxy or oxo, or E is xe2x80x94N(Rxe2x80x2)3xe2x80x94CH2xe2x80x94C(O)xe2x80x94 or the fragment 
wherein t is 2, 3, or 4, and W is CH or N, or Exe2x80x94N(Rxe2x80x2)1 taken together form the fragment 
wherein u is 1, 2 or 3; or a prodrug thereof.
Preferred compounds of formula (XX) are those wherein E is an L-amino acid with a hydrophobic side chain, serine, threonine or xe2x80x94N(Rxe2x80x2)3xe2x80x94CH2xe2x80x94C(O)xe2x80x94 or wherein Exe2x80x94N(Rxe2x80x2)1 taken together form the fragment 
Other preferred compounds have the formula (XX), wherein J is as previously defined; D is a bond, an amino-acid of the formula xe2x80x94NHxe2x80x94CH[(CH2)qC(O)OH]xe2x80x94C(O)xe2x80x94 or an ester derivative thereof and q being 0, 1, 2 or 3, xe2x80x94N((1-6C)alkyl)xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94N((2-6C)alkenyl)xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94N(benzyl)xe2x80x94CH2xe2x80x94COxe2x80x94, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain, which amino acid may optionally be N-(1-6C)alkyl substituted;
or J and D together are the residue (Rxe2x80x2)4(Rxe2x80x2)5Nxe2x80x94CH(Rxe2x80x2)6xe2x80x94C(O)xe2x80x94; and E is a cyclic amino acid optionally containing an additional heteroatom selected from N, O or S, and optionally substituted with (1-6C)alkyl, (1-6C)alkoxy, benzyloxy or oxo, or E is xe2x80x94N(Rxe2x80x2)3xe2x80x94CH2xe2x80x94C(O)xe2x80x94 or the fragment 
More preferred compounds of formula (XX) are those wherein J is H, 2-hydroxy-3-cyclohexyl-propionyl-, 9-hydroxy-fluorene-9-carboxyl, (Rxe2x80x2)2, (Rxe2x80x2)2xe2x80x94SO2xe2x80x94, (Rxe2x80x2)7OOCxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94SO2xe2x80x94, (Rxe2x80x2)7OOCxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94, (Rxe2x80x2)32Nxe2x80x94COxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94, Hetxe2x80x94COxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94 wherein Het contains as a heteroatom at least a nitrogen atom which is bound to CO, or an N-protecting group, wherein (Rxe2x80x2)2 is selected from (1-12C)alkyl, (2-12C)alkenyl, (6-14C)aryl, (7-15C)aralkyl and (8-16)aralkenyl which groups may optionally be substituted (1-6C)alkoxy; each group (Rxe2x80x2)3 is independently H or has the same meaning as (Rxe2x80x2)2; (Rxe2x80x2)7 has,the same meaning as (Rxe2x80x2)3 or is morpholino-(1-6C)alkyl or morpholino-(2-6C)alkynyl; D is a bond, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain, which amino acid may optionally be N-(1-6C)alkyl substituted; or J and D together are the residue (Rxe2x80x2)4(Rxe2x80x2)5Nxe2x80x94CH(Rxe2x80x2)6xe2x80x94C(O)xe2x80x94.
Most preferred are the compounds of formula (XX) wherein J is H, (Rxe2x80x2)2xe2x80x94SO2xe2x80x94, (Rxe2x80x2)7OOCxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94, (Rxe2x80x2)12Nxe2x80x94COxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94, 
D is a bond, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain; or J and D together are the residue (Rxe2x80x2)4(Rxe2x80x2)5Nxe2x80x94CH(Rxe2x80x2)6xe2x80x94C(O)xe2x80x94, wherein at least one of (Rxe2x80x2)4 and (Rxe2x80x2)5 is (Rxe2x80x2)7OOCxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94 or (Rxe2x80x2)2xe2x80x94SO2xe2x80x94 and the other independently is (1-12C)alkyl, (2-12C)alkenyl, (2-12C)alkynyl, (3-12C)cycloalkyl, (7-15C)aralkyl, (Rxe2x80x2)2xe2x80x94SO2xe2x80x94 or (Rxe2x80x2)7OOCxe2x80x94(CH(Rxe2x80x2)3)pxe2x80x94, and (Rxe2x80x2)6 is a hydrophobic side chain.
Preferably, the group Q in the compounds of formula (XX) has one of the structures: 
wherein X is O or S.
Like the compounds of formula (I), the compounds of formula (XX) have an anticoagulant effect and are useful for treating and preventing thrombin-mediated and thrombin-associated diseases, applicable as herein before described.
In the description of the compounds of the formula (XX), the following definitions are used. The term optionally substituted D,L xcex1-hydroxyacetyl means a group of the formula HOxe2x80x94CRaRbxe2x80x94C(O)xe2x80x94, wherein Ra and Rb independently are H, a hydrophobic side chain, or Ra and Rb together form a 5- or 6-membered ring, which is optionally fused with one or two aliphatic or aromatic 6-membered rings, and which 5- or 6-membered ring consists of carbon atoms and optionally one heteroatom selected from N, O and S. Preferred D,L xcex1-hydroxyacetyl groups are 2-hydroxy-3-cyclohexyl-propionyl- and 9-hydroxy-fluorene-9-carboxyl.
The term (1-12C)alkyl means a branched or unbranched alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl, t-butyl, isopentyl, heptyl, dodecyl, and the like. Preferred alkyl groups are (1-6C)alkyl groups, having 1-6 carbon atoms.
A (2-12C)alkenyl group is a branched or unbranched unsaturated hydrocarbon group having 2 to 12 carbon atoms. Preferred are (2-6C)alkenyl groups. Examples are ethenyl, propenyl, allyl, and the like.
The term (1-6C)alkylene means a branched or unbranched alkylene group having 1 to 6 carbon atoms, such as xe2x80x94(CH2)bxe2x80x94 and b is 1 to 6, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH(CH3)xe2x80x94(CH2)xe2x80x94, etc.
A (2-12C)alkynyl group is a branched or unbranched hydrocarbon group containing a triple bond and having 2 to 12 carbon atoms Preferred are (2-6C)alkynyl groups, such as ethynyl and propynyl.
A (6-14C)aryl group is an aromatic moiety of 6 to 14 carbon atoms. The aryl group may further contain one or more hetero atoms, such as N, S, or O, also referred to as heteroaryl groups. Examples of aryl groups are phenyl, naphthyl, (iso)quinolyl, indanyl, and the like. Most preferred is the phenyl group.
(7-15C)Aralkyl and (8-16C)aralkenyl groups are alkyl and alkenyl groups respectively, substituted by one or more aryl groups, the total number of carbon atoms being 7 to 15 and 8 to 16, respectively.
The term (1-6C)alkoxy means an alkoxy group having 1-6 carbon atoms, the alkyl moiety of which having the meaning as previously defined.
The term (3-12C)cycloalkyl means a mono- or bicycloalkyl group having 3-12 carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl, the camphor group, etc. Cyclopentyl and cyclohexyl are preferred cycloalkyl groups.
The term halogen means fluorine, chlorine, bromine or iodine.
The term ester derivative means any appropriate ester derivative, preferably (1-4C)alkyl-esters, such as methyl-, ethyl- or t-butyl-esters.
The terms 1- and 3-Tiq mean 1,2,3,4-tetrahydroisoquinoline-1- and -3-carboxylic acid, respectively; 1- and 3-Piq are perhydroisoquinoline-1- and -3-carboxylic acid, respectively; Atc is 2-aminotetralin-2-carboxylic acid; Aic is amino indane carboxylic acid; Phe is phenylalanine; Cha is cyclohexylalanine; Dpa is diphenylalanine; Coa is cyclooctylalanine; Chg is cyclohexylglycine; Nle is norleucine, Asp is aspartic acid.
The term hydrophobic side chain means a (1-12C)alkyl, optionally substituted with one or more (3-12C)cycloalkyl groups or (6-14C)aryl groups (which may contain a heteroatom, e.g. nitrogen) such as cyclohexyl, cyclo-octyl, phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, and the like, which hydrophobic side chain may optionally be substituted with substituents such as halogen, trifluoromethyl, lower alkyl (for instance methyl or ethyl), lower alkoxy (for instance methoxy), phenyloxy, benzyloxy, and the like.
In the definitions, the term substituted in general means: substituted by one or more substituent. Amino acids having a basic side chain are for example, but not limited to, arginine and lysine, preferably arginine. The term amino acids having a neutral side chain refers to amino acids such as methionine sulphon and the like.
Cyclic amino acids are for example 2-azetidine carboxylic acid, proline, pipecolic acid, 1-amino-1-carboxy-(3-8C)cycloalkane (preferably 4C, 5C or 6C), 4-piperidine carboxylic acid, 4-thiazolidine carboxylic acid, 3,4-dehydro-proline, azaproline, 2-octahydroindole carboxylic acid, and the like Preferred are 2-azetidine carboxylic acid, proline, pipecolic acid, 4-thiazolidine carboxylic acid, 3,4-dehydro-proline and 2-octahydroindole carboxylic acid.
Also preferred serine protease inhibitors of the present invention are compounds of the formula (XXX): 
in which formula Q is as previously defined; r is an integer of 0 to 4; (Rxe2x80x3)1 is a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxy group or an alkoxycarbonylalkoxy group; (Rxe2x80x3)2 is a hydrogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group, M is an alkylene group having a carbon number of 1 to 4, which may have 1 or 2 substituents selected from the group consisting of hydroxyalkyl, carboxyl, alkoxycarbonyl, carboxyalkyl and alkoxycarbonylalkyl; T is a single bond, an oxygen atom, a sulfur atom or a carbonyl group; K is a saturated or unsaturated 5- or 6-membered heterocyclic moiety or cyclic hydrocarbon moiety optionally having a substituent group, an amino group optionally having a substituent group or an aminoalkyl group optionally having a substituent group.
Related compounds are known for instance from EP 0,540,051. According to the present invention the compounds of EP 0,540,051 are altered by replacing the aromatic group carrying the amidine substituent by the group Q, thus improving in particular the absorptive properties of the compounds, such as examples having the structure: 
Like the compounds of the structures (I) and (XX), the compounds of structure (XXX) show a strong anticoagulant effect and are applicable as herein described.
In the compounds of the present invention represented by general formula (XXX), any straight chain, branched chain or cyclic alkyl group having 1 to 6 carbon atoms may be used as the lower alkyl group. Illustrative examples include methyl, ethyl, propyl, isopropyl, butyl, sec- or tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The lower alkoxy group may have 1 to 6 carbon atoms. Illustrative examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec- or tert-butoxy and the like. The alkoxycarbonyl, carboxyalkyl, alkoxycarbonylkalkyl, carboxyalkoxy, alkoxycarbonylalkoxy and hydroxyalkyl groups preferably have 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, respectively. Illustrative examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like. Illustrative examples of the carboxyalkyl group include carboxymethyl, carboxyethyl, carboxypropyl and the like. Illustrative examples of the alkoxycarbonylalkyl group include methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, methoxycarbonylpropyl, ethoxycarbonylpropyl and the like. Illustrative examples of the carboxylalkoxy group include carboxymethoxy, carboxyethoxy, carboxypropoxy and the like. Illustrative examples of the alkoxycarbonylalkoxy group include methoxycarbonylmethoxy, ethoxycarbonylmethoxy, propoxycarbonylmethoxy, methoxycarbonylethoxy, ethoxycarbonylethoxy and the like. Illustrative examples of the hydroxyalkyl group include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and the like. The saturated or unsaturated 5- or 6-membered heterocyclic moiety may contain preferably one or two hetero-atom(s) selected from nitrogen and oxygen atoms. Illustrative examples of such a preferred type of heterocyclic rings include pyrrolidine, piperidine, imidazoline, piperazine, tetrahydrofuran, hexahydropyrimidine, pyrrole, imidazole, pyrazine, pyrrolidinone, piperidinone, morpholine and the like. More preferable are pyrrolidine and piperidine which contain one nitrogen atom as the hetero-atom. Illustrative examples of the saturated or unsaturated cyclic hydrocarbon moiety include cyclopentyl, cyclohexyl and the like. Illustrative examples of the aminoalkyl group include aminomethyl, aminoethyl, aminopropyl and the like. Illustrative examples of the substituents applicable to these heterocyclic moieties and cyclic hydrocarbon moieties include preferably lower alkyl, lower alkanoyl, carbamoyl, mono- or dialkylcarbamoyl, formimidoyl, alkanoimidoyl, benzimidoyl, carboxyl, alkoxycarbonylimino and the like, more preferably formimidoyl and alkanoimidoyl groups. Illustrative examples of the substituents applicable to these amino groups and amino moieties of aminoalkyl groups include preferably lower alkyl, pyradinyl, pyrrolidinyl, carbamoyl, mono- or dialkylcarbamoyl, lower alkanoyl, formimidoyl, alkanoimidoyl, benzimidoyl, alkoxycarbonyl and the like, more preferably pyrazinyi, pyrrolidinyl, formimidoyl, alkanoimidoyl groups. In this instance, each of the alkyl, alkoxy, alkanoyl and the like listed above may preferably have a carbon number of from 1 to 6.
Other preferred serine protease inhibitors of the present invention are compounds of the formula (XL): 
in which formula (Rxe2x80x2xe2x80x3)1 and (Rxe2x80x2xe2x80x3)2 are independently H, lower alkyl, aryl, heteroaryl, cycloalkyl or lower alkyl substituted by one or more substituents selected from CONH2, COO-(lower alkyl), aryl, heteroaryl and cycloalkyl; or (Rxe2x80x2xe2x80x3)2 is lower alkanoyl; (Rxe2x80x2xe2x80x3)3 is H, COOH, CONH2, COO-(lower alkyl), CONH-(lower alkyl) or CON(lower alkyl)2; (Rxe2x80x2xe2x80x3)4, (Rxe2x80x2xe2x80x3)5 and (Rxe2x80x2xe2x80x3)6 are independently H, lower alkyl, aryl, aralkyl or cycloalkyl; or (Rxe2x80x2xe2x80x3)4 and/or one of (Rxe2x80x2xe2x80x3)5 and (Rxe2x80x2xe2x80x3)6 is heteroaryl or lower alkyl substituted with OH, SO2H, SO3H, guanidino, aryl-(lower alkoxy), lower alkoxy or lower alkylthio; or (Rxe2x80x2xe2x80x3)2 together with (Rxe2x80x2xe2x80x3)4 forms a tri- or tetramethylene group, in which (a) a methylene group may be replaced by S, SO or SO2 or may be substituted with OH, lower alkyl, lower alkenyl or carboxy-(lower alkyl) or (b) one of the methylene groups may be substituted with lower alkenyl and the other with (lower alkyl)-COOH; and at least one of (Rxe2x80x2xe2x80x3)1, (Rxe2x80x2xe2x80x3)2, (Rxe2x80x2xe2x80x3)4, (Rxe2x80x2xe2x80x3)5 and (Rxe2x80x2xe2x80x3)6 is the group of formula Q, Q having the previously defined meaning.
Related compounds are known from EP 0,728,758. The present invention is an improvement in the art when compared to these known compounds because of the presence of the specific group Q for introducing the favourable properties as herein before described.
Like the compounds of the structures (I), (XX) and (XXX), the compounds of structure (XL) show anticoagulant activity and are applicable as herein described. The compounds of structure (XL) display this effect in particular through their specific thrombin- and FXa-inhibiting activity.
In the description of compounds of formula (XL) the term xe2x80x9clowerxe2x80x9d means a branched or unbranched group having 1-6 C-atoms. Preferred lower alkyl or lower alkanoyl groups contain up to 4 C-atoms, e.g. methyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and acetyl, respectively. xe2x80x9cArylxe2x80x9d alone or in combination means groups like phenyl, which may be substituted, for instance with amidino, guanidino, hydroxyamidino, nitro, amino or methylenedioxy. xe2x80x9cAralkylxe2x80x9d means an aryl bound to a lower alkyl, e.g. a benzyl group, substituted in the phenyl ring, or phenylethyl. xe2x80x9cCycloalkylxe2x80x9d means saturated groups having 3-7 C-atoms, like cyclohexyl. xe2x80x9cHeteroarylxe2x80x9d means 5- to 10 membered aromatic groups, which may consist of two rings, and contain one (or more) N-atom(s) and may be substituted, e.g. ,by one or more NH2-groups. An example is chinazolinyl, such as 2,4-diaminochinazolin-6- or 7-yl. Examples of groups having amino, guanidino or N-hydroxyamidino substituents are amino-substituted chinazolinyl and (amino, amidino, guanidino or N-hydroxyamidino)-substituted phenyl, benzyl and lower alkyl groups.
Further preferred compounds according to the invention are the GpIIb/IIIa antagonists of the formula (L):
Qxe2x88x92[spacer]xe2x88x92COOHxe2x80x83xe2x80x83(L),
wherein Q has the previously defined meaning; the distance between the amino substituted carbon atom of the group Q and the carbon atom of the carboxylate moiety has a length of 12-18 xc3x85; the spacer is any suitable chemical moiety; and the carboxylate group may be esterified. The compounds of structure (L) show anticoagulant effect and are applicable as herein described.
From literature it is known, that a large group of spacers are suitable for the above purpose, provided that the length thereof is restricted (see Bioorg. and Med. Chemistry Letters, 7(2), 209-212, (1997), and references cited therein). Examples of compounds of formula (L) are derived from the following known compounds, in which the benzamidine moiety has been replaced by the group Q (but not limited to these examples): the compounds Ro 43-8857 (J. Med. Chem. 35, 4393 (1992)), Ro 44-9883, Ro 48-3657, Fradafiban, BIBL 12, FK-633, GR 144053, EMD 76 334, SR 121566, SB 208651, SC 54684, SC 54701, SC 52012, DMP 754, GPI 562 and compounds described in EP 529,858, WO 96/20172, EP 496,378, EP 530,505, Bioorg. and Med Chem. 3, 539 (1995), WO 93/08174 and J.Am.Chem.Soc. 115, 8861 (1993). This replacement by the group Q in the above compounds results in an improvement of the pharmacological properties of the compounds, in particular of the absorptive properties in the intestines, as herein described.
Preferred compounds of formula (L) have the formula (La):
Qxe2x80x94C(O)xe2x80x94N(Rxe2x80x3xe2x80x3)1xe2x80x94Uxe2x80x94C(Rxe2x80x3xe2x80x3)1(Rxe2x80x3xe2x80x3)2xe2x80x94Vxe2x80x83xe2x80x83(La),
wherein Q has the previously defined meaning; (Rxe2x80x3xe2x80x3)1 is independently H or (1-4C)alkyl; U is a bond, CH(Rxe2x80x3xe2x80x3)1; (Rxe2x80x3xe2x80x3)2 is (1-12C)alkyl, (2-12C)alkenyl, (2-12C)alkynyl, (3-8C)cycloalkyl, (6-14C)aryl, (7-15C)aralkyl or (8-16)aralkenyl, which may optionally be substituted with (1-6C)alkyl, (3-8C)cycloalkyl, (1-6C)alkoxy, OH, COOH, CF3 or halogen;V is a 5-, 6-, or 7-membered saturated, unsaturated or aromatic ring which may optionally contain one or more heteroatoms selected from O, N or S and which ring is substituted with one or two substituents selected from xe2x80x94(CH2)vxe2x80x94COO(Rxe2x80x3xe2x80x3)1 and xe2x80x94Oxe2x80x94(CH2)vxe2x80x94COO(Rxe2x80x3xe2x80x3)1, v being 1, 2, 3 or 4.
More preferred compounds of formula (La) are those wherein m is 0; U is a bond; (Rxe2x80x3xe2x80x3)2 is (1-4C)alkyl, phenyl or benzyl, which may optionally be substituted with OH or halogen and V is phenyl, piperidinyl, piperazinyl or thiazolyl, substituted with one substituent selected from xe2x80x94CH2xe2x80x94COO(Rxe2x80x3xe2x80x3)1 and xe2x80x94Oxe2x80x94CH2xe2x80x94COO(Rxe2x80x3xe2x80x3)1.
Other preferred compounds of the formula (L) have the formula (Lb)
Qxe2x80x94Z1xe2x80x94C(O)xe2x80x94N(Rxe2x80x3xe2x80x3)3xe2x80x94Z2xe2x80x94[C(O)]yxe2x80x94CH(Rxe2x80x3xe2x80x3)4xe2x80x94(CH2)zxe2x80x94COO(Rxe2x80x3xe2x80x3)3xe2x80x83xe2x80x83(Lb)
wherein Q has the previously defined meaning; Z1 is a bond, Cxe2x95x90C or Cxe2x89xa1C; (Rxe2x80x3xe2x80x3)3 is H or (1-4C)alkyl; Z2 is selected from 
(Rxe2x80x3xe2x80x3)4 is H, (1-12C)alkyl, (2-12C)alkenyl, (2-12C)alkynyl, (3-8C)cycloalkyl, (6-14C)aryl (7-15C)aralkyl or (8-16)aralkenyl, which may optionally be substituted with (1-6C)alkyl, (3-8C)cycloalkyl, (1-6C)alkoxy, OH, COOH, CF3 or halogen; y is 0 or 1 and z is 0 or 1.
More preferred are the compounds of formula (Lb) wherein Z1 is Cxe2x95x90C; Z2 is 
(Rxe2x80x3xe2x80x3)4 is H; y is 1 and z is 0.
Other preferred compounds of the formula (L) have the formula (Lc)
Qxe2x80x94N(H)xe2x80x94C(O)xe2x80x94Fxe2x80x94C(O)xe2x80x94N(Rxe2x80x3xe2x80x3)5xe2x80x94(CH2)fxe2x80x94N(Rxe2x80x3xe2x80x3)5xe2x80x94CH2COOHxe2x80x83xe2x80x83(Lc),
wherein Q has the previously defined meaning;
(Rxe2x80x3xe2x80x3)5 is independently H, (1-4C)alkyl or benzy or both (Rxe2x80x3xe2x80x3)5 groups are an ethylene bridge to form a 6- or 7-membered ring together with Nxe2x80x94(CH2)uxe2x80x94N to which they are bound; F is Cxe2x95x90C, or 1,2-, 1,3- or 1,4-phenylene, or 1,2-(4-5C)heteroarylene, 2,3-naphthylene or 1,2-(5-7C)cycloalkylene, which groups may optionally be substituted with (1-4C)alkyl; and f is 2 or 3.
The terms used in the definitions of the compounds of formula (L), (La), (Lb) and (Lc) have the same meaning as those used for the compounds of formula (XX).
The present invention further relates to the finding that also in other therapeutic compounds the presence of the group Q gives rise to an improved pharmacological profile. Especially when Q is used to replace a basic moiety in compounds of which is known that they require such a moiety for their therapeutic activity, an improvement of the absorptive properties is observed, in particular when that basic moiety is a (hetero)arylguanidino or (hetero)arylamidino moiety. Preferred therapeutic compounds of the invention have an apparent Caco-2 permeability of 8 nm/s or higher. Preferably the group Q has the formula 
m being as previously defined.
The compounds of the invention may be used in a broad range of therapeutic applications which require oral administration of a drug or wherein oral administration thereof is considered favourable, such as in particular (but not limited to) CNS-active compounds, compounds useful for treating immunological disorders, antithrombotic agents, and the like. Preferred compounds of the present invention are antithrombotic agents.
The term xe2x80x9ctherapeutic compoundxe2x80x9d as used herein means any compound which can be used in therapy, which implies the curing of a disease or malfunction of the body and which covers prophylactic treatment.
Compounds of the present invention wherein Q has the formula 
wherein the substructure 
is a structure selected from 
wherein X is O or S;
Xxe2x80x2 being independently CH or N; and m is 0, 1, 2 or 3; can be prepared using suitable starting compounds and methods as described in the literature e.g. 4-amino-6-chloroquinazoline and 4-amino-7-chloroquinazoline as described by A. Rosowsky and N. Papathanasopoulos in J. Heterocycl. Chem. 9, 1235 (1972); 4-aminothieno[2,3d]pyridazine or 7-aminothieno[2,3d]pyridazine by M. Robba, B. Roques and Y. Le Guen in Bull. Soc. Chim. France 4220, (1967); 4-aminothieno[2,3d]pyrimidine by M. Robba, J.-M. Lecompte and M. Cugnon de Sevricourt in Bull. Soc. Chim. France 592, (1975); 4-aminothieno[3,2d]pyrimidine by M. Robba, J.-M. Lecompte and M. Cugnon de Sevricourt in Tetrahedron 27, 487, (1971); 4-amino-6-bromothieno[2,3d]pyrimidine by M. Robba, J.-M. Lecompte and M. Cugnon de Sevricourt in Bull. Soc. Chim. France 761, (1976); 4-amino-6-bromoquinazoline by M. F. G. Stevens and A. Kreutzberger in Angew. Chem. 81, 84, (1969).
The compounds of the present invention wherein Q has the formula 
wherein m is 0, 1, 2 or 3 and X is CHxe2x95x90CH, O or S, can be prepared using compounds of formula (II). 
A suitable method starts from a compound of formula (III) (wherein the halogen atom, if present, preferably is Br), the hydroxy group of which is chlorinated, e.g. by treatment with POCl3, to give the compound of formula (IV), followed by conversion into the amino analogue of formula (II) , for example by first converting the chloro-substituent into a phenoxy-substituent by reaction with phenol under alkaline conditions, and subsequently treatment with ammonium acetate, or by direct conversion of the chloro-compound into the corresponding amino-compound by heating the former with ammonia under pressure. 
The compound of formula (IV) in this sequence, wherein X is CHxe2x95x90CH and the halogen is Br, may also be prepared by converting the corresponding unsubstituted compound into the N-oxide salt, e.g. with a peracid, such as m-chloroperbenzoic acid, followed by HCl treatment, and subsequently reacting this N-oxide salt with a chlorinating reagent, like POCl3.
Compounds according to formula (I) can be prepared by deprotection of the following compound (e.g. by saponification)
R1xe2x80x94Yxe2x80x94[NR2xe2x80x94Axe2x80x94C(O)]nxe2x80x94NR3xe2x80x94CHR4xe2x80x94C(O)xe2x80x94Oxe2x80x94G,
wherein G e.g. is an alkyl or benzyl group, followed by coupling with R5xe2x80x94H, or they can be prepared by deprotection of the compound
Pgxe2x80x94NR3xe2x80x94CHR4xe2x80x94C(O)R5,
wherein Pg is an N-protecting group, followed by coupling with one of the groups
R1xe2x80x94Yxe2x80x94NR2xe2x80x94Axe2x80x94C(O)xe2x80x94OH, R1xe2x80x94Yxe2x80x94Lg or R1xe2x80x94C(O)xe2x80x94OH, wherein Lg is a leaving group.
Compounds of formula (I) wherein R4 is Q may be prepared starting with a compound of formula (V), 
or a derivative thereof wherein the amino group at the aromatic group (arylamino) is protected, wherein X and R3 have the previously defined meanings. The carboxylic acid group of a compound of formula (V) is esterified, e.g. by treatment with R6OH and thionyl chloride, wherein R6 has the previously defined meaning, to form a compound of formula (VI), or an arylamino protected derivative thereof. 
A compound of formula (VI) is converted into a compound of formula (Ia), being the compound of formula (I) wherein R5 is OR6, or an arylamino protected derivative thereof, either by coupling to R1YLg (Lg is a leaving group) (n=0), for example by reaction with R1YCl under basic conditions, e.g. by using triethylamine, or by peptide coupling with R1YNR2AC(O)OH (n=1) or R1C(O)OH (n=0) using as a coupling reagent for example N,N-dicyclohexylcarbodiimide (DCCI) and 1-hydroxybenzotriazole (HOBT) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), wherein R1, R2, Y, n and A have the previously defined meanings. The protective group, if present, may optionally be removed. 
The ester group of a compound of formula (Ia) or an arylamino protected derivative thereof may be saponified to form the corresponding acid, after which the protective group, if present, may optionally be removed. The acid formed from a compound of formula (Ia) may be coupled to an amine of formula HNR7R8, wherein R7 and R8 have the previously defined meanings, for example by using DCCI/HOBT or TBTU, followed by removal of the optionally present protective group, to give a compound of formula (Ib), which is the compound of formula (I), wherein R5 is NR7R8. 
An alternative procedure for the preparation of a compound of formula (Ib) starts with the protection of the N-terminus of a compound of formula (V) with an N-protecting group Pg, such as Boc (tert-butoxycarbonyl), forming a compound of formula (VII), where also the arylamino group may be protected. 
Subsequently, a compound of formula (VII) is coupled to an amine of formula HNR7R8 according to the procedure as described above for the conversion of a compound of formula (Ia) into (Ib), after which the N-terminus is deprotected, followed by a coupling to R1YLg (n=0), or by peptide coupling with R1YNR2AC(O)OH (n=1) or R1C(O)OH (n=0) according to the procedures as described above for the conversion of a compound of formula (VI) into a compound of formula (Ia), followed by removal of the optionally present protective group, giving the compound of formula (Ib).
A suitable process for the preparation of the compound of formula (V) is the conversion of a compound of formula (VIII), wherein Pg is an N-protecting group and Lg is a leaving group, such as the mesyl group, into a compound of formula (IX), for example by reaction with an appropriate amino acid derivative of the general formula PgR3Nxe2x80x94CH[C(O)OR]2 in the presence of a base, e.g [[(1,1-dimethylethoxy)carbonyl]amino] propanedioic acid diethyl ester in the presence of sodium ethoxide, wherein Pg and R3 have the previously defined meanings and both Pg-groups may be the same or different, and R is a branched or unbranched (1-8C)alkyl group, such as ethyl. (If here R3 is H, the amino group may be alkylated later in the procedure according to methods well known in the art to form compounds wherein R3 is alkyl.) Hydrolysis and decarboxylation of a compound of formula (IX) gives a compound of formula (V). 
The compound according to formula (VIII) may be prepared by methods known in the art. The arylamino group of a compound of formula (II) is protected with an N-protecting group, after which the ring wherein X is located is provided with a formyl substituent either by treatment with a base, like lithium diisopropylamide, or with an organometallic reagent, like n-butyllithium, followed by addition of N,N-dimethylformamide, forming a compound of formula (X). (For compounds wherein m is 2 or 3, appropriate analogues of a compound of formula (X) may be prepared by this method which subsequently may be converted according the procedures as described for the conversion of a compound of formula (X)) 
The compound of formula (X) is reduced, e.g. using sodium borohydride, into the corresponding alcohol, which then is converted into a leaving group, e.g. an appropriate sulfonate group, thereby forming a compound of formula (VIII).
Compounds of formula (X) are suitable intermediates for the preparation of compounds of formula (I) wherein R3 is Q. In those preparations a compound of formula (X) is reacted with an appropriate amino acid derivative of the general formula NH2xe2x80x94CHR4xe2x80x94C(O)OR, R4 and R having the previously defined meanings. The resulting imine is either directly converted into a compound of formula (XI) by reduction, using e.g. sodium cyanoborohydride, or isolated and subsequently reduced with an suitable reducing agent like sodium borohydride to form a compound of formula (XI).
An alternative procedure for the preparation of a compound of formula (XI) starts from a compound of formula (VIII) by substitution of Lg by an appropriate amino acid derivative of the general formula NH2xe2x80x94CHR4xe2x80x94C(O)OR. 
Compounds of formula (XI) are then converted into compounds of formula (Ic), the compounds of formula (I) wherein R3 is Q and R5 is OR6, by a procedure analogous to the preparation of compounds of formula (Ia) from compounds of formula (VI) followed by removal of the protective group. 
From compounds of formula (Ic) compounds of formula (Id) are prepared, which are the compounds of formula (I), wherein R3 is Q and R5 is NR7R8, following the procedure as described for the conversion of (Ia) into (Ib). 
Alternatively, a compound of formula (Id) may be obtained after protection of the N-terminus of (XI) with an N-protecting group Pg, such as Boc, both protecting groups in the molecule being the same or different, and saponification of the ester group to give intermediate (XII), and further derivatization as described for the conversion of a compound of formula (VII) into a compound of formula (Ib). 
Compounds of formula (I) wherein R12 together with R3 is xe2x80x94(CH2)sxe2x80x94 can be prepared from amines of formula (VI) wherein R3 is hydrogen and the arylamino-is optionally protected. Reaction of these amines with aldehydes of formula Pg(R2)NCH((CH2)(s-1)CHO)COOG, wherein Pg is a N-protecting group and R2, s and G have the previously defined meanings, gives imides which are reduced using e.g. sodium cyanoborohydride to give cyclic compounds of formula (XIII). After removal of the N-protecting group Pg the moiety,R1Y can be introduced as described for the conversion of compounds of formula (VI) into compounds of formula (Ia). The group OR6 can be modified in the same way as described for the conversion of compounds of formula (Ia) into compounds of formula (Ib) and removal of protecting groups if present gives compounds of formula (Ie), Furthermore, compounds of formula (Ie) and (XIII) can be prepared using the methods described by H. Mack et al. in J. Enzyme Inhibition 9, 73 (1995), wherein instead of the cyanophenyl building blocks used in the literature, building blocks containing moiety Q or a arylamino protected derivative thereof (e.g. compounds of formula (VI)) can be used. 
Compounds of formula (XX) can be prepared from compounds of formula (X). Reaction of a compound of formula (X) with an amine of formula (Rxe2x80x2)1NH2 gives an imide, which is either directly converted into a compound of formula (XXI) by reduction, using e.g. sodium cyano borohydride, or is isolated and subsequently reduced with a suitable agent like sodium borohydride to form a compound of formula (XXI), wherein (Rxe2x80x2)1 has the previously defined meanings. 
Alternatively a compound of formula (X) is reduced, using e.g. sodium borohydride, into the coresponding alcohol which then is converted into an azide using the method described by A. S. Thompson et al. in J. Org. Chem. 58, 5886 (1993). This azide can be reduced into an amine using reagents known in the art such as Pd/CaCO3 catalyzed hydrogenation to yield a compound of formula (XXI) in which (Rxe2x80x2)1 is hydrogen.
A compound of formula (XXI), or a derivative thereof wherin the arylamino is not protected, can be coupled with carboxylate compounds of formula Jxe2x80x94Dxe2x80x94Exe2x80x94OH, in which J, D and E have the previously defined meanings, or a protected derivative thereof, using peptide coupling methods. Subsequent removal of the optionally present protective groups gives compounds of formula (XX).
Compounds of formula (XXa) can be prepared by reaction of amines of formula (XXI), wherein (Rxe2x80x2)1 is hydrogen with aldehydes of formula PgHNCH((CH2)(u-1)CHO)COOG, wherein Pg is a N-protecting group and u and G have the previously defined meanings, using the method described for compounds of formula (Ie). 
Compounds of formula (XXX) may be prepared in several ways in which the synthetic connection of moiety Q and the substituted phenyl part is made in moiety M. The method described in EP 0540051 may be used to prepare componds of formula (XXX) starting with compounds of formula (VIII).
Compounds of formula (XL) can be prepared by reaction of a compound of formula (XLI) with a compound of formula (XLII) and a compound of formula (XLIII), wherein (Rxe2x80x2xe2x80x3)1, (Rxe2x80x2xe2x80x3)2, (Rxe2x80x2xe2x80x3)5, and (Rxe2x80x2xe2x80x3)6 have the previously defined meanings according to the methods described in EP 0728758. When (Rxe2x80x2xe2x80x3)1 or (Rxe2x80x2xe2x80x3)2 is the group of formula Q compounds of formula (II), (VIII) or (X) or an arylamino protected derivative thereof can be used to prepare compounds of formula (XLI) or (XLII). When (Rxe2x80x2xe2x80x3)4 is the group of formula Q amino acids of formula (VI) or an arylamino protected derivative thereof can be used as starting materials, When (Rxe2x80x2xe2x80x3)5 or (Rxe2x80x2xe2x80x3)6 is the group of formula Q, compounds of formula (X) or an arylamino protected derivative thereof can be used as a starting material, being aldehydes of formula (XLIII), or used to prepare ketones of formula (XLIII). 
Compounds of formula (L) can be prepared using methods known in the art described for Gp IIb/IIIa receptor antagonists containing a (hetero)arylamidine moiety instead of moiety Q. Compounds of formula (La) can conveniently be prepared from compounds of formula (X). An aldehyde of formula (X) is oxidized, using e.g. sodium chlorite, into the corresponding carboxylic acid. This carboxylic acid, or a derivative thereof wherein at the arylamino is not protected, can be coupled with an amine linker of formula HN(Rxe2x80x3xe2x80x3)1xe2x80x94Uxe2x80x94(Rxe2x80x3xe2x80x3)1(Rxe2x80x3xe2x80x3)2xe2x80x94V or a N-protected derivative thereof, wherein (Rxe2x80x3xe2x80x3)1, (Rxe2x80x3xe2x80x3)2-and V have the previously defined meanings, using peptide coupling methods (e.g. using the amines and methods described in J. Med. Chem. 35, 4393 (1992), EP 0,505,868 or J. Med. Chem. 39, 3193 (1996)). Subsequent removal of the optionally present protective groups gives compounds of formula (La). Using a similar peptide coupling conditions a linker molecule having one free carboxylate can also be coupled with compound of formula (XXI), or a derivative thereof wherein the arylamino is not protected. Subsequent removal of the optionally present protective groups gives compounds of formula (L). Also halogen containing compounds of formula (II) can be used as starting material. The linker molecule can be attached using Pd mediated reactions such as Suzuki coupling, Heck reaction, or first transmetalation, using e.g. n-BuLi, and secondly reaction with a linker molecule containing an electrophilic function. Subsequent removal of the optionally present protective groups gives compounds of formula (L). For instance, Heck reaction of a halogen containing compound of formula (II) and an acrylic acid derivative leads to compounds of formula (Lb). An alternative method for the preparation of compounds of formula (Lb) is a condensation reaction of aldehydes of formula (X) with a malonic acid derivative. Modification of this malonic acid derivative using methods known in the art and subsequent removal of optionally present protecting groups yields compounds of formula (Lb).
Compounds of the invention can also be prepared using a solid phase synthesis strategy. To prepare componds of formula (Ia) the carboxylic acid of the compounds of formula (VII) can be covalently attached to a polymeric support such as a polystyrene-resin using a ester or amide bond as anchoring bond. In this case protection of the arylamino function is preferred. For example anchoring using a ester bond to the Kaiser oxime resin, Boc-protection of the N-terminus and acetyl amide protection of the arylamino group. The N-terminus protecting group can be removed selectively followed by coupling to R1YLg (n=0), or by peptide coupling with R1C(O)OH (n=0), Pg2NR2AC(O)OH (n=1) or R1YNR2AC(O)OH (n=1) according to the procedures described above for the conversion of compounds of formula (VI) into compounds of formula (Ia). Protecting group Pg2 is a protecting group that can be removed selectively. Removal of Pg2 liberates the N-terminus which can be coupled with R1YLg (n=0), or with R1C(O)OH (n=0) by peptide coupling methods according to the procedures described above for the conversion of compounds of formula (VI) into compounds of formula (Ia). Cleavage of the anchoring bond and removal of protecting groups, if present, gives compounds of formula (Ia) or (Ib) depending on the type of anchoring bond and way of cleavage used. For example cleavage of the anchoring ester bond to the Kaiser oxime resin with amines of type HNR7R8 followed by removal of the optionally present protective groups yields compounds of formula (Ib).
The solid phase synthesis strategy outlined above starting from compounds of formula (VII) can also be applied using the carboxylic acid of compounds of formula (XII) to yield compounds of formula (Ic) or (Id). Further, this strategy can be applied to carboxylic acids of formula Jxe2x80x94Dxe2x80x94Exe2x80x94OHxe2x80x94 in which J, D, and E have the previously defined meaningsxe2x80x94, a synthetic precursor thereof or a protected derivative thereof. Cleavage of the anchoring bond to the Kaiser oxime resin using amines of formula (XXI) yields compounds of formula (XX) after removal of the optionally present protecting group.
Alternatively, the arylamino functionality of moiety Q can be used to be covalently attached to a polymeric support using e.g. a carbamate functionality as method of anchoring and used in a solid phase synthesis.
Several solid-phase synthesis strategies especially in the solid-phase synthesis of peptides are known in the art. An overview of solid-phase peptide synthesis is given by P. Lloyd-Williams, F. Albericio and E. Giralt in Tetrahedron 48, 11065-11133 (1993).
The peptide coupling, as mentioned as a procedural step in the above described method to prepare the compounds of the invention, can be carried out by methods commonly known in the art for the couplingxe2x80x94or condensationxe2x80x94of peptide fragments such as by the azide method, mixed anhydride method, activated ester method, or, preferably, by the carbodiimide method, especially with the addition of catalytic and racemisation suppressing compounds like N-hydroxy-succinimide and N-hydroxybenzotriazole. An overview is given in The Peptides, Analysis. Synthesis, Biology, Vol 3, E. Gross and J. Meienhofer, eds. (Academic Press, New York, 1981).
The term N-protecting group as used in this whole document means a group commonly used in peptide chemistry for the protection of an xcex1-amino group, like the tert-butyloxycarbonyl (Boc) group, the benzyloxycarbonyl (Z) group, the 9-fluorenylmethyloxycarbonyl (Fmoc) group or the phthaloyl (Phth) group. Removal of the protecting groups can take place in different ways, depending on the nature of those protecting groups. Usually deprotection takes place under acidic conditions and in the presence of scavengers. An overview of amino protecting groups and methods for their removal is given in the above mentioned The Peptides, Analysis, Synthesis Biology, Vol 3.
Suitable leaving groups (Lg) are known in the art, for example from A. L. Ternay: Contemporary Organic Chemistry (2nd ed., W. B. Saunders Company, 1979, see pages 158 and 170-172). Preferred leaving groups are chloride, mesylate and tosylate.
The compounds of the invention, which can occur in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as HCl, HBr, HI, H2SO4, H3PO4, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
The compounds of this invention may possess one or more chiral carbon atoms, and may therefore be obtained as a pure enantiomer, or as a mixture of enantiomers, or as a mixture containing diastereomers. Methods for obtaining the pure enantiomers are well known in the art, e.g. crystallization of salts which are obtained from optically active acids and the racemic mixture, or chromatography using chiral columns.
The compounds of the invention may be administered enterally or parenterally. The exact dose and regimen of these compounds and compositions thereof will neccessarily be dependent upon the needs of the individual subject to whom the medicament is being administered, the degree of affliction or need and the judgment of the medical practitioner. In general parenteral administration requires lower dosages than other methods of administration which are more dependent upon absorption. However, the daily dosages are for humans preferably 0.001-100 mg per kg body weight, more preferably 0.01-10 mg per kg body weight.
The medicament manufactured with the compounds of this invention may also be used as adjuvant in acute anticoagulant therapy. In such a case, the medicament is administered with other compounds useful in treating such disease states.
The compounds may also be used with implantable pharmaceutical devices such as those described in U.S. Pat. No. 4,767,628, the contents of which are incorporated by this reference. Then the device will contain sufficient amounts of compound to slowly release the compound (e.g. for more than a month).
Mixed with pharmaceutically suitable auxiliaries, e.g. as described in the standard reference, Gennaro et al., Remington""s Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture) the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied in the form of a solution, suspension, emulsion, e.g. for use as an injection preparation, or as a spray, e.g. for use as a nasal spray.
For making dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.
Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
The invention is further illustrated by the following examples.